Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation.
The clearance of native human placental glucocerebrosidase by rat liver shows the presence of two distinct enzyme forms with different recognition characteristics. The clearance and uptake of native enzyme by liver cells was compared to that of glucocerebrosidase sequentially treated with neuraminidase, beta-galactosidase and beta-N-acetylglucosaminidase. The initial rate of clearance of infused enzyme was increased greater than 10-fold for the asialo-, agalacto- and ahexoenzymes over that of native glucocerebrosidase. Incorporation of asialo enzyme was increased in hepatocytes over that of native enzyme, while the distribution of agalacto- and ahexoenzyme preparations was increased in non-parenchymal cells. This observation is consistent with the identification of a galactose receptor on hepatocytes and N-acetylglucosamine/mannose receptors on Kupffer cells. These data and inhibition studies by specified monosaccharide-terminal glycoprotein derivatives demonstrate the importance of these sugars in the uptake of this lysosomal enzyme by receptor-mediated endocytosis. Modification of the enzyme to expose certain monosaccharide moieties results in increased delivery to specific cell types. Therefore, naturally occurring receptors can be utilized for targeting glucocerebrosidase to the non-parenchymal cell in liver.
D000118:Acetylglucosaminidase; D000818:Animals; D001692:Biological Transport; D005260:Female; D005959:Glucosidases / Q000378:metabolism*; D005962:Glucosylceramidase / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009439:Neuraminidase; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D001616:beta-Galactosidase
D005959:Glucosidases; D009439:Neuraminidase; D001616:beta-Galactosidase; D005962:Glucosylceramidase; D000118:Acetylglucosaminidase